PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia, and also an age-related neurological disorder. AD not only causes severe distress for patients and caregivers, but it also becomes a major public health predicament. However, the mechanisms responsible for the pathogenesis of AD are still unclear, which is a major challenge for AD prevention and therapy. Increasing evidence suggests that dysfunctional and aging immune system may be a primary factor/inducer for the development of AD. Accumulated regulatory T (Treg) cells and senescent T cells have been identified in AD patients, but the functional roles of these T cell populations in the pathogenesis of AD are poorly understood. Furthermore, the causative relationship between Treg and senescent T cells in AD development and progression is unknown. We recently discovered a novel suppressive mechanism that human Treg cells can induce responder nave and effector T cell senescence. Importantly, our more recent studies demonstrated that senescent T cells can promote the aggregation of amyloid precursor protein (APP), amyloid beta (A?) and Tau proteins in human neuronal cells. Therefore, an improved understanding of the molecular and cellular processes of senescent T cells in the pathogenesis of AD is urgently needed, which could lead to the development of novel and effective therapeutic strategies. The central hypotheses of this proposal are: 1) accumulated Treg cells induce senescence among T cells thereby promoting the development and pathogenesis of AD; 2) blockage of senescence in T cells is a critical checkpoint to control AD pathologic processes and progression, which will provide a novel strategy for AD prevention and immunotherapy. Specific Aim 1 seeks to determine whether senescent T cells induced by Treg cells are a critical player for the pathogenesis of AD in vivo in animal models. Aim 2 will first investigate whether and how senescent T cells reprogram the metabolism and functions of differentiated and undifferentiated neuronal cells. We will then identify the unique senescence-associated secretory phenotype (SASP) of senescent T cells, including inflammatory cytokines and metabolites, responsible for the functional changes in neurons induced by senescent T cells, resulting in neurodegeneration and AD development. Aim 3 will further propose complementary in vivo studies to test our hypothesis and the novel concept that reversal of T cell senescence through the inhibition of ATM signaling and/or MAPK signaling can prevent AD development and mitigate AD pathology in a spontaneous senescence accelerated mouse model. A positive outcome of these studies should lead to novel strategies for molecular control of T cell fate and function for AD prevention and immunotherapy.